Early in the city's history, many foreign countries opened their embassies on 16th Street because of its proximity to the White House. Many religious denominations followed with churches, earning the street the nickname "Church Row." These include Foundry Methodist (attended by Presidents Hayes and Clinton), First Baptist (attended by Presidents Truman and Carter), the Nineteenth Street Baptist Church which was originally named the First Colored Baptist Church of Washington, D.C. (visited twice by President Barack Obama), St. John's ("Church of the Presidents"), All Souls Unitarian, Universalist National Memorial Church, St. John the Baptist Russian Orthodox Cathedral,founded in 1949 and built in 1958, and Third Church of Christ, Scientist, which was designed by an associate of I.M. Pei in 1972.[2]Shrine of the Sacred Heart is located just off of 16th Street. After most of the embassies moved to Embassy Row and other parts of the city, the churches became more prominent in 16th Street's identity.

The northern and central portions of 16th Street — and the Crestwood neighborhood, in particular — have for a half century been the chosen neighborhood of accomplished African Americans in Washington. Known colloquially as "The Gold Coast", these sections of 16th Street are lined with early 20th-century Tudor mansions.[3]

The street's proximity to Rock Creek Park and importance as a thoroughfare has made it a natural dividing boundary for Washington neighborhoods. Outside of the downtown area, no neighborhood in the city falls on both sides of 16th Street; the neighborhoods that surround it have 16th as either their eastern or their western boundary. For many years, the wide street was the de facto boundary between Caucasian and African-American neighborhoods of the city, especially in the tense years after the 1968 race riots; today this is less true.

A pair of similarly named streets, 16th Street Northeast and 16th Street Southeast, are three miles (5 km) away in the northeast and southeast quadrants of Washington. They are contiguous with each other and parallel to 16th Street NW.